Treatment of the CNS effects of HIV

ABSTRACT

Methods and compositions for treating the central nervous system (CNS) effects of HIV, particularly AIDS related dementia.

TECHNICAL FIELD OF THE INVENTION

Methods and compositions for treating the central nervous system (CNS)effects of HIV, particularly AIDS related dementia.

BACKGROUND OF THE INVENTION

The human immunodeficiency virus ("HIV") is the causative agent foracquired immunodeficiency syndrome ("AIDS")--a disease characterized bythe destruction of the immune system, particularly of CD4⁺ T-cells, withattendant susceptibility to opportunistic infections--and its precursorAIDS-related complex ("ARC")--a syndrome characterized by symptoms suchas persistent generalized lymphadenopathy, fever and weight loss.

As in the case of several other retroviruses, HIV encodes the productionof a protease which carries out post-translational cleavage of precursorpolypeptides in a process necessary for the formation of infectiousvirions (S. Crawford et al., "A Deletion Mutation in the 5' Part of thepol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processingof the gag and pol Polyproteins", J. Virol., 53, p. 899 (1985)). Thesegene products include pol, which encodes the virion RNA-dependent DNApolymerase (reverse transcriptase), an endonuclease, HIV protease,(reverse transcriptase), an endonuclease, HIV protease, and ga, whichencodes the core-proteins of the virion (H. Toh et al., "CloseStructural Resemblance Between Putative Polymerase of a DrosophilaTransposable Genetic Element 17.6 and pol gene product of Moloney MurineLeukemia Virus", EMBO J., 4, p. 1267 (1985); L. H. Pearl et al., "AStructural Model for the Retroviral Proteases", Nature, pp. 329-351(1987); M. D. Power et al., "Nucleotide Sequence of SRV-1, a Type DSimian Acquired Immune Deficiency Syndrome Retrovirus", Science, 231, p.1567 (1986)).

A number of synthetic anti-viral agents have been designed to targetvarious stages in the replication cycle of HIV. These agents includecompounds which block viral binding to CD4⁺ T-lymphocytes (for example,soluble CD4), and compounds which interfere with viral replication byinhibiting viral reverse transcriptase (for example, didanosine andzidovudine (AZT)) and inhibit integration of vital DNA into cellular DNA(M. S. Hirsh and R. T. D'Aqulia, "Therapy for Human ImmunodeficiencyVirus Infection", N. Eng. J. Med., 328, p. 1686 (1993)). However, suchagents, which are directed primarily to early stages of viralreplication, do not prevent the production of infectious virions inchronically infected cells. Furthermore, administration of some of theseagents in effective amounts has led to cell-toxicity and unwanted sideeffects, such as anemia and bone marrow suppression.

More recently, the focus of anti-viral drug design has been to createcompounds which inhibit the formation of infectious virions byinterfering with the processing of viral polyprotein precursors.Processing of these precursor proteins requires the action ofvirus-encoded proteases which are essential for replication (Kohl, N. E.et al. "Active HIV Protease is Required for Viral Infectivity" Proc.Natl. Acad. Sci. USA, 85, p. 4686 (1988)). The anti-viral potential ofHIV protease inhibition has been demonstrated using peptidal inhibitors.Such peptidal compounds, however, are typically large and complexmolecules that tend to exhibit poor bioavailability and are notgenerally consistent with oral administration. Accordingly, the needstill exists for compounds that can effectively inhibit the action ofviral proteases, for use as agents for preventing and treating chronicand acute vital infections.

AIDS and other HIV related diseases often have CNS components. One suchcomponent is AIDS related dementia.

While there are a growing number of treatments for HIV and its relateddiseases, e.g., AIDS and ARC, such treatments have had little or noeffect on the CNS effects of HIV infection.

The reason that these treatments are not as effective against the CNSeffects of HIV is that the pharmaceutical compositions that characterizethem are not able to cross the blood brain barrier in an amountsufficient to the effect and slow HIV infection in the CNS.

AZT, the most well-known of the HIV treatments, for example, has abrain/blood distribution of only about 0.3. And after 60 minutes, no AZTis found in brain tissue. The other HIV nucleosides, ddC, DDI and d4T,have even worse distribution profiles in the CNS.

HIV protease inhibitors also do not penetrate to the CNS at usefullevels. Abbott's ABT 538, for example, displays very limited CNSpenetration. Searle's inhibitor has a brain/blood distribution of 0.2 to0.3. Merck's L-535524 has about the same distribution.

Thus, the present HIV nucleoside and protease based therapies have lessthan desired effects on the CNS components of HIV.

SUMMARY OF THE INVENTION

This invention provides a method and a composition for treating the CNScomponents of HIV, particularly AIDS related dementia.

The method and composition of this invention are characterized by an HIVprotease inhibitor of Formula I: ##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compound of Formula I is an HIV protease inhibitor. However, unlikeother protease inhibitors, it has a brain/blood distribution of morethan 1.0. This means that it is very effective in crossing theblood/brain barrier. In fact, it is present in the brain at about thesame level as it is present in the blood. In addition, the compound ofFormula I has an unexpectedly long half life in the brain. Both of theseproperties result in the compound of Formula I being unexpectedly usefulin treating the CNS effects of HIV, particularly AIDS related dementia.

The compound of Formula I can be made from available starting materialsusing any one of several well known synthetic routes. Examples of suchsyntheses include those described in International Patent Application WO94/05639, which is hereby incorporated by reference.

In general, sulfonamides of formula I are conveniently obtained fromα-amino acid derivatives having the general formula P-N(G)-CH(D)-COOH,wherein P is defined as THF-O-C(O)-- or an amino acid protecting group,D is defined as benzyl, and G is H or benzyl. Suitable amino acidprotecting groups are described in numerous references, including T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2dEd., John Wiley and Sons (1991). Examples of such amino acid protectinggroups include, but are not limited to, carbamate containing groups suchas Boc, Cbz or Alloc, or alternatively, the amine may be protected as analkyl derivative such as N,N-dibenzyl or trityl. Such α-amino acidderivatives are often commercially available or may be convenientlyprepared from commercially available α-amino acid derivatives usingknown techniques. Although this invention envisions the use of racemicmixtures of such starting materials, a single enantiomer in the Sconfiguration is preferred.

Using known techniques, the α-amino acid derivative of general formulaP-N(G)-CH(D)-COOH may be readily converted to an amino ketone derivativeof general formula P-N(G)-CH(D)-CO-CH₂ -X, wherein X is a leaving groupwhich suitably activates the α-carbon (i.e., increases thesusceptibility of the methylene to nucleophilic attack). Suitableleaving groups are well known in the art and include halides andsulfonates, such as methanesulfonate, trifluoromethanesulfonate or4-toluenesulfonate. X may also be a hydroxyl which is converted in situto a leaving group (e.g. by treatment with a trialkyl- ortriarylphosphine in the presence of a dialkylazodicarboxylate). Methodsfor the formation of such amino ketone derivatives also are well knownto those of skill in the art (see, for example, S. J. Fittkau, J. Prakt.Chem., 315, p. 1037 (1973)). Alternatively, certain amino ketonederivatives are commercially available (e.g., from Bachem Biosciences,Inc., Philadelphia, Pa.).

The amino ketone derivative may then be reduced to the correspondingamino alcohol, represented by the formula P-N(G)-CH(D)-CH(OH)-CH₂ -X.Alternatively, the amino ketone derivative can be reduced later in thesynthetic scheme. Many techniques for reduction of amino ketonederivatives such as P-N(G)-CH(D)-CO-CH₂ -X are well known to those ofordinary skill in the art (Larock, R. C. "Comprehensive OrganicTransformations", pp. 527-547, VCH Publishers, Inc.© 1989 and referencescited therein). A preferred reducing agent is sodium borohydride. Thereduction reaction is conducted at a temperature of from about -40° C.to about 40° C. (preferably, at about -10° C. to about 20° C.), in asuitable solvent system such as, for example, aqueous or neattetrahydrofuran or a lower alcohol, such as methanol or ethanol.Although this invention envisions both stereospecific andnon-stereospecific reduction of the amino ketone derivativeP-N(G)-CH(D)-CO-CH₂ -X, stereoselective reduction is preferred.Stereoselective reduction may be accomplished by use of chiral reagentsknown in the art. In the present invention, stereoselective reductionmay be conveniently achieved, for instance, under non-chelating reducingconditions, where chiral induction of the newly formed hydroxyl group isset by the stereochemistry of the D group (i.e., Felkin-Ahn addition ofhydride). We particularly prefer stereoselective reductions wherein theresulting hydroxyl is syn to D. We have found that when the hydroxylgroup is syn to D, the final sulfonamide product is an HIV proteaseinhibitor of higher potency than the anti diastereomer.

The hydroxyl group of the amino alcohol may optionally be protected byany known oxygen protecting group (such as trialkylsilyl, benzyl, oralkyloxymethyl) to yield a protected amino alcohol having the formulaP-N(G)-CH(D)-C(OR⁷)-CH₂ -X, wherein R⁷ is H or any suitable hydroxyprotecting group. Several useful protecting groups are described in T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2dEd., John Wiley and Sons (1991).

This protected amino alcohol may then be reacted with a nucleophilicamine compound to form an intermediate of formula III: ##STR2## whereinP is defined as THF-O-C(O)- or an amino acid protecting group, D isbenzyl, R⁷ is as described above, and L is either isobutyl or hydrogen.

Alternatively, an appropriately protected and activated amino acidderivative may be reacted with a nucleophilic nitro compound (e.g., anitromethane anion or a derivative thereof), which after coupling, canbe reduced to yield an intermediate of formula III.

In a particularly advantageous synthetic scheme, simultaneous activationof the methylene and protection of the alcohol may be accomplished byforming an N-protected amino epoxide from the oxygen and its adjacentmethylene to give an intermediate of formula II: ##STR3## wherein P, Dand G are defined above. Suitable solvent systems for preparing theN-protected amino epoxide include anhydrous or aqueous organic solventssuch as ethanol, methanol, isopropanol, tetrahydrofuran, dioxane,dimethylformamide and the like (including mixtures thereof). Suitablebases for producing the epoxide include alkali metal hydroxides,potassium t-butoxide, DBU and the like. A preferred base is potassiumhydroxide.

Preferably, the compound of Formula I is made by preparing theN-protected amino epoxide by reacting the dianion of an acetic acidderivative containing a potential leaving group on the α-carbon with acyclic N-carboxyanhydride of a protected α-amino acid (such asBOC-Phe-NCA, available from Propeptide) or other appropriately protectedand activated amino acid derivative. This method incorporates the use ofhaloacetic acids or, generally, heteroatom-substituted acetic acidswherein the heteroatom may be converted to a leaving group. A preferredacetic acid dianion is (methylthio)acetic acid dianion. The resultingamino ketone may then be reduced (e.g., with sodium borohydride). In thecase where the nucleophile is the dianion of methylthioacetic acid, theresulting amino alcohol is readily converted to the amino epoxide byalkylation (e.g., with methyl iodide) followed by ring closure (using,for example, sodium hydride).

Reaction of the N-protected amino epoxide (or other suitably activatedintermediate) with an amine is carried out neat, i.e. in the absence ofsolvent, or in the presence of a polar solvent such as lower alkanols,water, dimethylformamide or dimethylsulfoxide. The reaction can becarried out conveniently between about -30° C. and 120° C., preferablybetween about -5° C. and 100° C. Alternatively, the reaction may becarried out in the presence of an activating agent, such as activatedalumina in an inert solvent, preferably an ether, such as diethyl ether,tetrahydrofuran, dioxane, or tert-butyl methyl ether, conveniently fromabout room temperature to about 110° C., as described by Posner andRogers, J. Am Chem. Soc., 99, p. 8208 (1977). Other activating reagentsinclude lower trialkyl-aluminum species, such as triethylaluminum, ordialkylaluminum halide species, such as diethylaluminum chloride(Overman and Flippin, Tetrahedron Letters, p. 195 (1981)). Reactionsinvolving these species are conveniently carried out in inert solventssuch as dichloromethane, 1,2-dichloroethane, toluene, or acetonitrilebetween about 0° C. and about 110° C. Further methods of displacingleaving groups, or opening epoxides with amines or their equivalentssuch as azides or timethylsilyl cyanide (Gassman and Guggenheim, J. Am.Chem. Soc. 104, p. 5849 (1982)), are known and will be apparent to thoseof ordinary skill in the art.

Compounds of formulae II and III, and functionality-protectedderivatives thereof, are useful as intermediates for the preparation ofthe compound of formula I. Where L represents isobutyl, compounds offormula III may be converted to the compound of formula I by reactionwith sulfonyl-activated species to form the sulfonamide. Methods forpreparing such sulfonyl-activated species are well within the ordinaryskill of the art. Typically, sulfonyl halides are used to obtainsulfonamides. Many sulfonyl halides are commercially available; othersmay be easily obtained using conventional synthetic techniques (Gilbert,E. E. "Recent Developments in Preparative Sulfonation and Sulfation"Synthesis 1969:3 (1969) and references cited therein; Hoffman, R. V."M-Trifluoromethylbenzenesulfonyl Chloride" Org. Synth. Coll. Vol. VII,John Wiley and Sons (1990); Hartman, G. D. et. al. "4-SubstitutedThiophene-and Furan-2-sulfonamides as Topical Carbonic AnhydraseInhibitors" J. Med. Chem., 35, p. 3822 (1992) and references citedtherein.

In the case of compounds of formula III wherein L is hydrogen,conversion of the resultant primary amine to a secondary amine may becarried out by known techniques. Such techniques include reaction withan alkyl halide or alkyl sulfonate, or by reductive alkylation with analdehyde using, for instance, catalytic hydrogenation or sodiumcyanoborohydride (Borch et al., J. Am. Chem. Soc., 93, p. 2897 (1971)).Alternatively, the primary amine may be acylated followed by reductionwith borane or another suitable reducing reagent, for example, asdescribed by Cushman et al., J. Org. Chem., 56, p. 4161 (1991). Thistechnique is especially useful in compounds of formula III where Prepresents a protecting group such as tert-butoxycarbonyl (Boc) orbenzyloxycarbonyl (Cbz) and G is hydrogen, or where P and G are bothbenzyl. ##STR4##

If variables P and G of a particular compound of formula IV representremovable protecting groups, removal of either or both groups followedby reaction of the resulting amine with an appropriate activated reagentwill advantageously yield a different compound of formula IV. Forinstance, carbamates may be obtained by reaction with chlorocarbonatesor with carbonates esterified with leaving groups such as1-hydroxybenzotriazole (HOBT) or HOSu, or 4-nitrophenol (protonatedspecies). An example of such a carbonate isN-succinimidyl-(3S)-tetrahydrofuran-3-yl carbonate. It will be readilyrecognized that in order to facilitate specific reactions, theprotection of one or more potentially reactive groups followed bysubsequent removal of that group may be required. Such modification tothe reaction schemes outlined above are within the ordinary skill of theart.

As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art.

The compound of this invention may be modified by appending appropriatefunctionalites to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compound of the present invention is an excellent ligand foraspartyl proteases, particularly HIV-1 and HIV-2 proteases. Accordingly,the compound is capable of targeting and inhibiting late stage events inHIV replication, i.e., the processing of the viral polyproteins by HIVencoded proteases. The compound inhibits the proteolytic processing ofvital polyprotein precursors by inhibiting aspartyl protease. Becauseaspartyl protease is essential for the production of mature virions,inhibition of that processing effectively blocks the spread of virus byinhibiting the production of infectious virions, particularly fromchronically infected cells. The compound according to this inventionadvantageously inhibits the ability of the HIV-1 virus to infectimmortalized human T cells over a period of days, as determined by anassay of extracellular p24 antigen--a specific marker of viralreplication. Other anti-viral assays have confirmed the potency of thiscompound.

The compound of this invention may be employed in a conventional mannerfor the treatment of viruses, such as HIV and HTLV, which depend onaspartyl proteases for obligatory events in their life cycle. Suchmethods of treatment, their dosage levels and requirements may beselected by those of ordinary skill in the art from available methodsand techniques. For example, the compound of this invention may becombined with a pharmaceutically acceptable adjuvant for administrationto a virally-infected patient in a pharmaceutically acceptable mannerand in an amount effective to lessen the severity of the viral infectionor to alleviate pathological effects associated with HIV infection.

Alternatively, the compound of this invention may be used inprophylactics and methods for protecting individuals against viralinfection during a specific event, such as childbirth, or over anextended period of time. The compound may be employed in suchprophylactics either alone or together with other antiretroviral agentsto enhance the efficacy of each agent. As such, the novel proteaseinhibitors of this invention can be administered as agents for treatingor preventing HIV infection in a mammal.

The compound of formula I may be readily absorbed into the bloodstreamof mammals upon oral administration. The compound of formula I having amolecular weight of less than about 600 g/mole and aqueous solubility ofgreater than or equal to 0.1 mg/mL is likely to demonstrate high andconsistent oral availability. This surprisingly impressive oralavailability makes the compound an excellent agent fororally-administered treatment and prevention regimens against HIVinfection.

In addition to being orally bioavailable, the compound of this inventionalso has an impressively high therapeutic index (which measures toxicityversus anti-viral effect). Accordingly, the compound of this inventionis effective at lower dosage levels than many previously describedconventional antiretroviral agents and avoid many of the severe toxiceffects associated with those drugs. The potential of this compound tobe delivered at doses far exceeding its effective antiviral level isadvantageous in slowing or preventing the possibility of resistantvariants developing.

The compound of this invention may be administered to a healthy orHIV-infected patient either as a single agent or in combination withother anti-vital agents which interfere with the replication cycle ofHIV. By administering the compound of this invention with otheranti-vital agents which target different events in the vital life cycle,the therapeutic effect of these compounds is potentiated. For instance,the co-administered anti-vital agent can be one which targets earlyevents in the life cycle of the virus, such as cell entry, reversetranscription and viral DNA integration into cellular DNA. Anti-HIVagents targeting such early life cycle events include, didanosine (ddI),dideoxycytidine (ddC), d4T, zidovudine (AZT), 3TC, 935U83, 1592U89,524W91, polysulfated polysaccharides, sT4 (soluble CD4), ganiclovir,trisodium phosphonoformate, eflornithine, ribavirin, acyclovir, alphainterferon and tri-menotrexate. Additionally, non-nucleoside inhibitorsof reverse transcriptase, such as TIBO, delavirdine (U90) or nevirapine,may be used to potentiate the effect of the compounds of this invention,as may viral uncoating inhibitors, inhibitors of trans-activatingproteins such as tat or rev, or inhibitors of the viral integrase.

Combination therapies according to this invention exert an additive orsynergistic effect in inhibiting HIV replication because each componentagent of the combination acts on a different site of HIV replication.The use of such combination therapies also advantageously reduces thedosage of a given conventional anti-retroviral agent which would berequired for a desired therapeutic or prophylactic effect, as comparedto when that agent is administered as a monotherapy. Such combinationsmay reduce or eliminate the side effects of conventional singleanti-retrovital agent therapies, while not interfering with theanti-retroviral activity of those agents. These combinations reducepotential of resistance to single agent therapies, while minimizing anyassociated toxicity. These combinations may also increase the efficacyof the conventional agent without increasing the associated toxicity. Inparticular, we have discovered that in combination with other anti-HIVagents, the compound of this invention acts in an additive orsynergistical manner in preventing the replication of HIV in human Tcells. Preferred combination therapies include the administration of thecompound of this invention with AZT, ddI, ddC, d4T, 3TC, 935U83,1592U89, 524W91 or a combination thereof.

Alternatively, the compound of this invention may also beco-administered with other HIV protease inhibitors such as saquinavir(Ro 31-8959, Roche), L-735,524 (Merck), ABT 538 (A-80538, Abbott), AG1341 (Agouron), XM 412 (DuPont Merck), XM 450 (DuPont Merck), BMS 186318(Bristol-Meyers Squibb) and CPG 53,437 (Ciba Geigy) or prodrugs of theseor related compounds to increase the effect of therapy or prophylaxisagainst various viral mutants or members of HIV quasi species.

We prefer administering the compound of this invention as a single agentor in combination with retroviral reverse transcriptase inhibitors, suchas derivatives of AZT, or other HIV aspartyl protease inhibitors,including multiple combinations comprising from 3-5 agents. We believethat the co-administration of the compound of this invention withretroviral reverse transcriptase inhibitors or HIV aspartyl proteaseinhibitors may exert a substantial additive or synergistic effect,thereby preventing, substantially reducing, or completely eliminatingvital replication or infection or both, and symptoms associatedtherewith.

The compound of this invention can also be administered in combinationwith immunomodulators and immunostimulators (e.g., bropirimine,anti-human alpha interferon antibody, IL-2, GM-CSF, interferon alpha,diethyldithiocarbamate, tumor necrosis factor, naltrexone, tuscarasol,and rEPO); and antibiotics (e.g., pentamidine isethiorate) to prevent orcombat infection and disease associated with HIV infections, such asAIDS and ARC.

When the compound of this invention is administered in combinationtherapies with other agents, they may be administered sequentially orconcurrently to the patient. Alternatively, pharmaceutical compositionsaccording to this invention may comprise a combination of an aspartylprotease inhibitor of this invention and another therapeutic orprophylactic agent.

Although this invention focuses on the use of the compound disclosedherein for preventing and treating HIV infection, the compound of thisinvention can also be used as an inhibitory agent for other viruseswhich depend on similar aspartyl proteases for obligatory events intheir life cycle. These viruses include other AIDS-like diseases causedby retroviruses, such as simian immunodeficiency viruses, HTLV-I andHTLV-II. In addition, the compound of this invention may also be used toinhibit other aspartyl proteases, and in particular, other humanaspartyl proteases, including renin and aspartyl proteases that processendothelin precursors.

The compositions of this invention are typically taken orally. Theycontain an amount of the compound of Formula I that is effective ininhibiting the replication of HIV by inhibiting its HIV protease in theCNS.

The compound of Formula I is employed in the method and composition ofthis invention in combination with a pharmaceutically acceptablecarrier. Typically, it is also used in combination with other AIDStherapies, particularly AZT and 3TC.

Pharmaceutical compositions of this invention comprise the compound ofthe present invention, and pharmaceutically acceptable salts thereof,with any pharmaceutically acceptable carrier, adjuvant or vehicle.Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asdα-tocopherol polyethyleneglycol 1000 succinate, serum proteins, such ashuman serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solublizedderivatives may also be advantageously used to enhance delivery of thecompound of formula I.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. We prefer oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant such as Ph. Helv or a similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, and aqueous suspensions and solutions. Inthe case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions are administered orally, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches arealso included in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

Dosage levels of between about 0.01 and about 100 mg/kg body weight perday, preferably between about 0.5 and about 75 mg/kg body weight per dayof the active ingredient compound are useful in the prevention andtreatment of viral infection, including HIV infection. Typically, thepharmaceutical compositions of this invention will be administered fromabout 1 to about 5 times per day or alternatively, as a continuousinfusion. Such administration can be used as a chronic or acute therapy.The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). Preferably, such preparations contain from about 20% to about 80%active compound.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

As the skilled artisan will appreciate, lower or higher doses than thoserecited above may be required. Specific dosage and treatment regimensfor any particular patient will depend upon a variety of factors,including the activity of the specific compound employed, the age, bodyweight, general health status, sex, diet, time of administration, rateof excretion, drug combination, the severity and course of theinfection, the patient's disposition to the infection and the judgmentof the treating physician.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLE 1

Precursor A. A solution of 102 mg of N-((2 syn, 3S )-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylaminobutylamine in 4:1 CH₂ Cl₂ /saturated aqueousNaHCO₃ was treated sequentially, at ambient temperature under anatmosphere of nitrogen, with 65 mg of p-nitrobenzenesulfonyl chlorideand 51 mg of sodium bicarbonate. The mixture was stirred for 14 h,diluted with CH₂ Cl₂, washed with saturated NaCl, then dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by lowpressure silica gel chromatography using 20% diethyl ether/CH₂ Cl₂ aseluent to provide 124 mg of the title product as a white solid. TLC:Rf=0.36, 20% diethyl ether/CH₂ Cl₂. HPLC: Rt=15.15 min. (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 2

Compound I. A solution of 124 mg of the resultant compound of Example 1in ethyl acetate was treated, at ambient temperature, with 13 mg of 10%palladium on carbon. The mixture was stirred for 14 h under anatmosphere of hydrogen, filtered through a pad of Celite filter agent,and concentrated in vacuo. The residue was subjected to preparative HPLCto yield 82 mg of the title product as a white solid. TLC: Rf=0.10, 20%ether/CH₂ Cl₂. HPLC: Rt=13.16 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

While we have described a number of embodiments of this invention, it isapparent that our basic constructions may be altered to provide otherembodiments which utilize the products and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims, rather than by the specificembodiments which have been presented by way of example.

I claim:
 1. A method for treating the CNS effects of HIV comprising the step of administering to a patient a pharmaceutical composition comprising a compound of Formula I: ##STR5## in an amount effective to inhibit HIV in the CNS.
 2. The method according to claim 1, wherein the composition further comprises AZT, 3TC or both. 